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Coronary artery disease review series
Antiplatelet therapy for secondary prevention of coronary artery disease
  1. Thomas Pilgrim,
  2. Stephan Windecker
  1. Department of Cardiology, Bern University Hospital, Bern, Switzerland
  1. Correspondence to Dr Stephan Windecker, Department of Cardiology, Bern University Hospital, Bern 3010, Switzerland; stephan.windecker{at}insel.ch

Abstract

The choice and duration of antiplatelet therapy for secondary prevention of coronary artery disease (CAD) is determined by the clinical context and treatment strategy. Oral antiplatelet agents for secondary prevention include the cyclo-oxygenase-1 inhibitor aspirin, and the ADP dependent P2Y12 inhibitors clopidogrel, prasugrel and ticagrelor. Aspirin constitutes the cornerstone in secondary prevention of CAD and is complemented by clopidogrel in patients with stable CAD undergoing percutaneous coronary intervention. Among patients with acute coronary syndrome, prasugrel and ticagrelor improve net clinical outcome by reducing ischaemic adverse events at the expense of an increased risk of bleeding as compared with clopidogrel. Prasugrel appears particularly effective among patients with ST elevation myocardial infarction to reduce the risk of stent thrombosis compared with clopidogrel, and offered a greater net clinical benefit among patients with diabetes compared with patients without diabetes. Ticagrelor is associated with reduced mortality without increasing the rate of coronary artery bypass graft (CABG)-related bleeding as compared with clopidogrel. Dual antiplatelet therapy should be continued for a minimum of 1 year among patients with acute coronary syndrome irrespective of stent type; among patients with stable CAD treated with new generation drug-eluting stents, available data suggest no benefit to prolong antiplatelet treatment beyond 6 months.

  • Coronary Artery Disease

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Introduction

Antiplatelet therapy represents an important pillar for secondary prevention of coronary artery disease (CAD) along with lifestyle modification and control of cardiovascular risk factors. Antiplatelet treatment strategies for the prevention of recurrent events are customised to clinical setting (acute coronary syndrome (ACS) versus stable CAD), patient comorbidities, and conservative versus invasive strategy, respectively. In this article we summarise the currently available evidence on choice, combination and duration of antiplatelet agents in various clinical settings.

Mechanisms of action of antiplatelet agents

Platelet activation and aggregation are part of the pathophysiological response to plaque rupture/erosion. Uncontrolled amplification loops may result in partial or complete thrombotic occlusion of coronary arteries resulting in ischaemia or infarction.1 Antiplatelet agents currently used in the secondary prevention of CAD target different receptors and interfere with various stages of platelet aggregation, providing a rationale for combination therapy.1 Mechanism of action, indications and potential interactions of antiplatelet agents used in secondary prevention of CAD are summarised in table 1. An overview on aspirin, thienopyridines and thienopyrimidines is provided in the online supplement.

Table 1

Summary of antiplatelet agents for secondary prevention

Secondary prevention in various clinical settings

Aspirin and clopidogrel have been investigated across the entire clinical spectrum of CAD. Randomised trials investigating the efficacy of antiplatelet agents for secondary prevention primarily focused on patients at high risk of cardiovascular events, namely patients with ACS, in which the beneficial effect is expected to be greatest. The novel ADP P2Y12 receptor antagonists prasugrel and ticagrelor have not been investigated in populations with stable CAD to date.

Stable CAD

Aspirin

Aspirin represents the cornerstone in secondary prevention of patients with stable CAD or ACS. In a randomised controlled trial aspirin was shown to reduce the rate of myocardial infarction early after percutaneous transluminal coronary angioplasty as compared with placebo (1.6% vs 6.9%, p=0.0113).2 Adherence to prolonged aspirin treatment was demonstrated to be effective for the prevention of myocardial infarction as compared with placebo in the Multi-Hospital Eastern Atlantic Restenosois Trial (M-HEART) with follow-up though 6 months.3

In a meta-analysis of the Antithrombotic Trialists’ Collaboration, treatment with aspirin at a dose of 75–150 mg daily reduced the incidence of serious vascular events by 33% in patients with stable CAD, and by 53% in patients undergoing percutaneous coronary intervention (PCI). Among patients with a history of myocardial infarction, aspirin therapy reduced the incidence of non-fatal reinfarction by 18 per 1000 patients, vascular death by 14 per 1000 patients, and non-fatal stroke by 5 per 1000 patients after a mean duration of follow-up of 27 months, with an excess of approximately 1 major extracranial bleed per 1000 patients per year. Secondary prevention with aspirin has been shown to reduce the yearly absolute risk of mortality from CAD by 34% and the risk of non-fatal myocardial infarction by 66%.4

Clopidogrel

Clopidogrel has been widely investigated for secondary prevention in patients with stable CAD undergoing conservative management5 ,6 or PCI.711

Long-term administration of clopidogrel at a daily dose of 75 mg showed a borderline significant reduction in the risk of vascular death, myocardial infarction or ischaemic stroke compared with aspirin at a dose of 325 mg daily in patients with atherosclerotic vascular disease (5.3%/year vs 5.8%/year, p=0.04).5 In the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial, clopidogrel was compared with placebo in addition to low-dose aspirin in 15 603 patients with cardiovascular disease or multiple risk factors.6 Although the primary end point of the overall cohort was not met, the combination of low-dose aspirin (75–162 mg/day) with clopidogrel (75 mg/day) resulted in a marginally significant reduction of the cumulative risk of myocardial infarction, stroke or cardiovascular death in the subset of patients with overt cardiovascular disease as compared with aspirin alone (6.9% vs 7.9%, risk ratio (RR) 0.88; 95% CI 0.77 to 0.998, p=0.046). This marginal benefit of dual antiplatelet therapy (DAPT) came at the expense of an increased risk of GUSTO moderate bleeding (2.1% vs 1.3%, p<0.001), discouraging the extended use of DAPT in patients with stable CAD undergoing conservative management.6 A separate analysis of the subgroup of patients with prior myocardial infarction, ischaemic stroke or symptomatic peripheral arterial disease showed similar results. In this cohort, the combination of aspirin and clopidogrel decreased the rate of cardiovascular death, myocardial infarction or stroke as compared with aspirin and placebo (7.3% vs 8.8%, HR 0.83, 95% CI 0.72 to 0.96, p=0.01), as well as the risk of hospitalisations for ischaemia (11.4% vs 13.2%, HR 0.86, 95% CI 0.76 to 0.96, p=0.008). The reduction of ischaemic end points was associated with an increased risk for GUSTO moderate (HR 2.0% vs 1.3%, HR 1.60, 95% CI 1.16 to 2.20, p=0.004), but not severe bleeding (1.7% vs 1.5%, HR 1.12, 95% CI 0.81 to 1.53, p=0.50).12 Long-term clopidogrel therapy may be a valid alternative in patients not tolerating aspirin, and in patients with very high atherosclerotic burden.

Among patients undergoing PCI, the combination of aspirin with the ADP P2Y12 receptor antagonist ticlopidine for the duration of 4–6 weeks considerably reduced ischaemic cardiovascular events as compared with the combination of aspirin with oral anticoagulation710 or aspirin monotherapy,9 and decreased the rate of haemorrhagic complications in comparison with combined oral anticoagulation.710 In the Clopidogrel for the Reduction of Events during Observation (CREDO) trial, prolonged dual antiplatelet treatment with clopidogrel for up to 1 year preceded by a 300 mg loading dose was associated with a 27% relative reduction in the risk of death, myocardial infarction or stroke (95% CI 3.9% to 44.4%, p=0.02) as compared with a short regimen of 1 month without loading dose, which came at the expense of a greater risk of major bleeding complications (8.8% vs 6.7%; p=0.07).11

Acute coronary syndromes

Characteristic clinical features of different antiplatelet agents for secondary prevention in patients with ACS are outlined in table 2. Evidence on antiplatelet treatment in the subgroup of patients with acute ST segment elevation myocardial infarction is summarised in more detail in the online supplement.

Table 2

Summary of secondary prevention for acute coronary syndromes in major trials and subanalyses

Aspirin

Several randomised trials compared aspirin with placebo in patients with non-ST elevation (NSTE)-ACS and showed a >50% reduction of the absolute risk of cardiac death and myocardial infarction in patients treated with aspirin. Among patients with ACS included into the Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events-Seventh Organization to Assess Strategies in Ischemic Syndromes (CURRENT-OASIS 7) trial, no difference between high-dose (300–325 mg four times a day) or low dose (75–100 mg four times a day) aspirin was documented with regards to a composite end point of cardiovascular death, myocardial infarction or stroke (4.2% vs 4.4%, HR 0.97, 95% CI 0.86 to 1.09, p=0.61), with no heterogeneity according to conservative treatment strategy or percutaneous revascularisation (p=0.93).13 Patients treated with low-dose aspirin experienced a lower rate of major gastrointestinal bleeding (0.2% vs 0.4%, p=0.04). Among patients undergoing PCI, high-dose aspirin showed no reduction in the primary outcome (4.1% vs 4.2%, HR 0.98, 95% CI 0.84 to 1.13, p=0.76), or the rate of major bleeding (1.5% vs 1.3%, HR 1.18, 95% CI 0.92 to 1.53, p=0.20).14

Clopidogrel

The role of clopidogrel for secondary prevention in patients with NSTE-ACS has been investigated among patients undergoing conservative management13 ,15 or PCI.14 ,16

In the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial the majority of patients (64%) with ACS did not undergo revascularisation after randomisation. Patients treated with clopidogrel in addition to aspirin for 3–12 months experienced a lower risk of the composite of cardiovascular death, non-fatal myocardial infarction or stroke as compared with patients in the placebo group (9.3% vs 11.4%, RR 0.80, 95% CI 0.72 to 0.90, p<0.001). No significant interaction with the treatment effect of revascularisation was documented.15

In the PCI-CURE study, a clopidogrel regimen consisting of pretreatment and continuation for 9 months was associated with a 31% reduction of cardiovascular death or myocardial infarction as compared with a 1 month regimen without pretreatment (8.8% vs 12.6%, RR 0.69, 95% CI 0.54 to 0.87, p=0.002).16

In the CURRENT-OASIS 7 trial the treatment effect of double dose clopidogrel (600 mg loading dose, followed by 75 mg twice daily for 1 week) was compared with a loading dose of 300 mg clopidogrel followed by a maintenance dose of 75 mg once daily in patients with ACS. There was no difference in the risk of cardiovascular death, myocardial infarction or stroke within 30 days between patients in the high-dose as compared with those assigned to the standard-dose regimen (4.2% vs 4.4%, HR 0.94, 95% CI 0.83 to 1.06, p=0.30). Major bleeding was more common among patients in the double-dose group as compared with the standard-dose group (2.5% vs 2.0%, HR 1.24, 95% CI 1.05 to 1.46, p=0.01). However, borderline heterogeneity with respect to the primary outcome was observed according to treatment strategy (p value for interaction=0.03).13 While no effect with regards to the primary end point was documented for double-dose clopidogrel among patients undergoing conservative management (n=7823), a prespecified analysis of the subset of patients undergoing PCI (n=17 263) demonstrated a reduction in the rate of the primary outcome (3.9% vs 4.5%, HR 0.86, 95% CI 0.74 to 0.99, p=0.039) and definite stent thrombosis (0.7% vs 1.3%, HR 0.54, 95% CI 0.39 to 0.74, p=0.0001).13 ,14 The reduction in ischaemic events came at the expense of an increased rate of major bleeding complications (1.6% vs 1.1%, HR 1.41, 95% CI 1.09 to 1.83, p=0.009).14

Prasugrel

In the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38), prasugrel (60 mg loading dose, 10 mg maintenance dose) has been compared with clopidogrel (300 mg loading dose, 75 mg maintenance dose) for 6–15 months in 13 608 clopidogrel-naïve patients undergoing PCI.17 The majority of patients was loaded with either prasugrel or clopidogrel within 1 h of completion of PCI. The primary composite efficacy end point of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke occurred less frequently among patients assigned to prasugrel as compared with those treated with clopidogrel (9.9% vs 12.1%, HR 0.81, 95% CI 0.73 to 0.90, p<0.001). The difference was already noted at the first prespecified time point of 3 days and was driven by a significant reduction in myocardial infarction in the prasugrel arm as compared with the clopidogrel arm (7.4% vs 9.7%, HR 0.76, 95% CI 0.67 to 0.85, p<0.001). In addition, lower rates of stent thrombosis (1.1% vs 2.4%, HR 0.48, 96% CI 0.36 to 0.64, p<0.001) and urgent target-vessel revascularisation (2.5% vs 3.7%, HR 0.66, 95% CI 0.54 to 0.81, p<0.001) were documented in patients receiving prasugrel. No difference in mortality rates were observed between patients treated with prasugrel or clopidogrel, respectively (3.0% vs 3.2%, HR 0.95, 95% CI 0.78 to 1.16, p=0.64). The effect of prasugrel came at the expense of an increased rate of major bleedings (2.4% vs 1.8%, HR 1.32, 95% CI 1.03 to 1.68, p=0.03) as well as life-threatening and fatal bleeding. In post hoc subgroup analyses, patients with a history of a cerebrovascular event, elderly patients ≥75 years, and patients with a body weight < 60 kg experienced no clinical benefit with prasugrel as compared with clopidogrel.17 A lower prasugrel maintenance dose might be applicable for those subgroups. In a prespecified analysis of the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) trial, no differences in ischaemic or bleeding outcomes with reduced-dose prasugrel (5 mg) was documented compared with clopidogrel among 2083 elderly patients ≥75 years undergoing conservative management for ACS.18 Moreover, no significant interactions for weight and bleeding risk were observed between reduced-dose prasugrel and standard-dose clopidogrel in elderly patients.19

The efficacy of prasugrel as compared with clopidogrel among patients with ACS undergoing conservative management has been investigated in the TRILOGY ACS trial. Among 7243 patients <75 years no difference with regards to the primary composite end point of cardiovascular death, myocardial infarction or stroke was reported between patients in the prasugrel group and the clopidogrel group, respectively (13.9% vs 16.0%, HR 0.91, 95% CI 0.79 to 1.05, p=0.21). Multiple recurrent events were however less frequent among patients treated with prasugrel (HR 0.85, 95% CI 0.72 to 1.00, p=0.04).18 In contrast to TRITON-TIMI 38 trial, rates of TIMI major bleeding were similar between the two treatment arms.18 Whereas no difference in the risk of cardiovascular death, myocardial infarction or stroke was documented among patients who did not undergo angiography (n=4158), prasugrel compared with clopidogrel was associated with a lower rate of the primary composite end point in the subgroup of patients undergoing angiography (n=3085) consistent with the findings in the TRITON-TIMI 38 trial (10.7% vs 14.9%, HR 0.77, 95% CI 0.61 to 0.98, p=0.032) (p for interaction=0.08).20

Ticagrelor

Ticagrelor (180 mg loading dose, 90 mg twice daily maintenance dose) has been compared with clopidogrel (300–600 mg loading dose, 75 mg maintenance dose) in 18 624 patients with ACS in the Platelet Inhibition and Patient Outcomes (PLATO) trial.21 Pretreatment with clopidogrel prior to study enrolment was allowed according to protocol, and DAPT was initiated prior to PCI in the majority of patients. At 12 months of follow-up, the rate of a composite of cardiovascular death, myocardial infarction and stroke was lower among patients in the ticagrelor arm as compared with the clopidogrel arm (9.8% vs 11.7%, HR 0.84, 95% CI 0.77 to 0.92, p<0.001). In addition, lower rates of myocardial infarction (5.8% vs 6.9%, HR 0.84, 95% CI 0.75 to 0.95, p=0.005), all-cause (4.5% vs 5.9%, HR 0.78, 95% CI 0.69 to 0.89, p<0.001) and cardiovascular mortality (4.0% vs 5.1%, HR 0.79, 95% CI 0.69 to 0.91, p=0.001) were observed among patients receiving ticagrelor.21 The reduction in the primary end point in favour of ticagrelor was apparent among patients with NSTE-ACS (11.4% vs 13.9%, HR 0.83, 95% CI 0.73 to 0.94); no beneficial effect of ticagrelor as compared with clopidogrel was however observed among patients with a final diagnosis of unstable angina (8.6% vs 9.1%, HR 0.96, 95% CI 0.75 to 1.22).22 While there were no differences in the overall rates of major bleeding (11.6% vs 11.2%, p=0.43), patients treated with ticagrelor had a higher risk of major bleeding not related to coronary artery bypass grafting (4.3% vs 3.8%, HR 1.19, 95% CI 1.02 to 1.38, p=0.03).21 The therapeutic benefit of ticagrelor over clopidogrel among patients with ACS with non-invasive management was consistent with the findings in the overall population of the PLATO-trial and showed a reduction in the composite primary end point (12.0% vs 14.3%, HR 0.85, 95% CI 0.73 to 1.00, p=0.04), as well as all-cause mortality (6.1% vs 8.2%, HR 0.75, 95% CI 0.61 to 0.93, p=0.01).23

No direct comparison between prasugrel and ticagrelor has been performed to date. Data from network meta-analyses suggested similar safety and efficacy of the two drugs, but indicated better protection from stent thrombosis with prasugrel at the expense of a higher rate of bleeding.24 ,25 Differences in the study designs and the context of the two trials however limit comparability of these findings. Whereas patients in PLATO were randomised prior to PCI irrespective of clopidogrel preloading, the majority of patients included into Trial to Assess Improvement in TRITON-TIMI 38 were randomised after angiography only.

Current European Society of Cardiology (ESC) guidelines on NSTE-ACS recommend ticagrelor in patients with moderate-to-high risk NSTE-ACS irrespective of the initial treatment strategy (IB) in the absence of contraindications. Prasugrel is recommended for moderate-to-high risk patients with NSTE-ACS with known coronary anatomy proceeding to PCI (IB) in addition to aspirin (IA). Clopidogrel is restricted to patients who cannot receive ticagrelor or prasugrel (IA). In contrast, in the 2012 American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) Guideline for the management of patients with unstable angina/NSTE-myocardial infarction clopidogrel and ticagrelor are on the same level of recommendation before PCI and along with prasugrel at the time of PCI.

Duration of dual antiplatelet treatment

Duration of dual antiplatelet treatment (DAPT) depends on clinical setting and stent type.

Acute coronary syndromes

In patients with an ACS (NSTE-ACS and ST-segment elevation myocardial infarction(STEMI)), DAPT is recommended for 1 year irrespective of treatment strategy (conservative vs invasive) according to the ESC guidelines, and for at least 12 months in patients undergoing PCI according to the 2012 ACCF/AHA guidelines. Prolonged DAPT has been associated with improved outcomes in studies comparing clopidogrel (9–12 months) with placebo15 and comparing prasugrel (median 14.5 months) or ticagrelor (median 9.2 months) with clopidogrel, respectively.17 ,21 However, DAPT has been associated with an increased risk of major bleeding as compared with monotherapy in studies with longer-term follow-up (HR 1.80, 95% CI 1.40 to 2.30) whereas a shorter course of DAPT had no effect on bleeding rates (HR 1.07, 95% CI 0.86 to 1.34).26

Data from a large contemporary registry of 56 440 patients indicated a lower rate of death, reinfarction and stroke with increasing duration of DAPT (65.2/1000 person-years for 3 months vs 45.3/1000 person-years for >3 months, HR 0.70, 95% CI 0.63 to 0.77, p<0.0001; 29.2/1000 person-years for 6 months vs 20.4/1000 person-years for >6 months, HR 0.70, 95% CI 0.56 to 0.87, p=0.0012). Rates of bleeding increased with increasing duration of DAPT (7.8/1000 person-years for 3 months vs 11.3/1000 person-years for >3 months, HR 1.45, 95% CI 1.14 to 1.86, p=0.0026).27 ,28

In view of the delicate balance between ischaemic and bleeding events as a function of comorbidities, the optimal duration of DAPT will depend on net clinical benefit in individual patients.

Stable coronary artery disease

Among patients with stable CAD the duration of DAPT is influenced by the stent type. While at least 1 month of DAPT is recommended after implantation of bare metal stents (BMS),29 the duration of DAPT after drug-eluting stents (DES) continues to be a matter of debate. A meta-analysis of four randomised trials demonstrated an increased risk of TIMI major bleeding for an extended duration of DAPT (HR 2.64, 95% CI 1.31 to 5.30, p=0.006) without a reduction of ischaemic events.30 Randomised trials investigating different regimens of DAPT are summarised in table 3, and might contribute towards changing current practice to a shorter duration of DAPT in the near future.

Table 3

Summary of studies on duration of dual antiplatelet therapy (DAPT)

New generation DES with thinner strut thickness, biocompatible polymers and lower drug doses, improve arterial healing which may mitigate the importance of prolonged platelet inhibition.

According to the guidelines on myocardial revascularisation by the European Society of Cardiology DAPT with aspirin (75–100 mg four times a day) (IB) and clopidogrel (75 mg four times a day) (IA) in the setting of stable CAD is recommended for at least 1 month in patients treated with BMS and for 6–12 months in patients after DES implantation. In the 2011 ACCF/AHA/SCAI Guideline for PCI clopidogrel is recommended for at least 12 months in patients treated with a DES and for a minimum of 1 month and ideally up to 12 months in patients treated with a BMS.

Secondary prevention in special populations

Antiplatelet treatment for secondary prevention may be particularly challenging in special populations such as patients with diabetes, patients requiring antithrombotic therapy and patients undergoing non-cardiac surgery. We refer to the online supplement for a detailed review of the current evidence in those patient populations.

References

View Abstract

Supplementary materials

  • Supplementary Data

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Footnotes

  • Contributors TP and SW performed the literature search and drafted the manuscript. SW is responsible for the overall content as guarantor.

  • Competing interests TP has received travel expenses and payment for lectures from Biotronik. SW has received research contracts to the institution from Biotronik and St Jude.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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